Chapter Navigation
- Introduction (definitions and sources of drugs) PH1.1, PH1.59
- Routes of drug administration PH1.11
- Pharmacokinetics PH1.4
- Pharmacodynamics
- Factors modifying drug action
- Drug interactions PH1.8
- Rational use of medicines
- Adverse drug effects PH1.7
- Treatment of poisoning PH1.52
- Poison information centres
- Pharmacoeconomics PH1.60
- New drug development PH1.64
Book Chapter
General pharmacology - Pharmacology for Medical Graduates, 4th Updated Edition
Pharmacology for Medical Graduates, 4th Updated Edition, CHAPTER 1, 1-45
Introduction (definitions and sources of drugs) PH1.1, PH1.59
- ■
Pharmacology: It is the science that deals with the effects of drugs on living systems.
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Drug: World Health Organization (WHO) defines drug as ‘ any substance or product that is used or intended to be used to modify or explore physiological systems or pathological states for the benefit of the recipient ’.
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Pharmacokinetics: It means the movement of drug within the body; it includes the processes of absorption (A), distribution (D), metabolism (M) and excretion (E). It means ‘what the body does to the drug’.
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Pharmacodynamics: It is the study of drugs – their mechanism of action, pharmacological actions and their adverse effects. It covers all the aspects relating to ‘what the drug does to the body’.
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Pharmacy: It is the branch of science that deals with the preparation, preservation, standardization, compounding, dispensing and proper utilization of drugs.
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Therapeutics: It is the aspect of medicine concerned with the treatment of diseases.
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Chemotherapy: It deals with treatment of infectious diseases/cancer with chemical compounds that cause relatively selective damage to the infecting organism/cancer cells.
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Toxicology: It is the study of poisons, their actions, detection, prevention and treatment of poisoning.
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Clinical pharmacology: It is the systematic study of a drug in man, both in healthy volunteers and in patients. It includes the evaluation of pharmacokinetic and pharmacodynamic data, safety, efficacy and adverse effects of a drug by comparative clinical trials.
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Essential medicines: According to WHO, essential medicines are ‘ those that satisfy the healthcare needs of majority of the population ’. They should be of assured quality, available at all times, in adequate quantities and in appropriate dosage forms. They should be selected with regard to disease prevalence in a country, evidence on safety and efficacy, and comparative cost-effectiveness. The examples are iron and folic acid preparations for anaemia of pregnancy, antitubercular drugs like isoniazid, rifampicin, pyrazinamide, ethambutol, etc.
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Orphan drugs: Drugs that are used for diagnosis, treatment or prevention of rare diseases. The expenses incurred during the development, manufacture and marketing of drug cannot be recovered by the pharmaceutical company from selling the drug, e.g. digoxin antibody (for digoxin toxicity), fomepizole (for methyl alcohol poisoning), etc.
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Over-the-counter drugs (OTC drugs, nonprescription drugs): These drugs can be sold to a patient without the need for a doctor’s prescription, e.g. paracetamol, antacids, etc.
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Prescription drugs: These are drugs which can be obtained only upon producing the prescription of a registered medical practitioner, e.g. antibiotics, antipsychotics, etc.
Sources of drug information
Pharmacopoeia : It is a book which contains a list of established and officially approved drugs with description of their physical and chemical characteristics and tests for their identification, purity, methods of storage, etc. Some of the pharmacopoeias are the Indian Pharmacopoeia (IP), the British Pharmacopoeia (BP), and the United States Pharmacopoeia (USP).
Other sources of drug information are National Formulary (NF), Martindale – the Extra Pharmacopoeia, Physician’s Desk Reference (PDR), American Medical Association Drug Evaluation, textbooks and journals of pharmacology and therapeutics, drug bulletins, databases like Micromedex, Medline, Cochrane Library, etc. Information can also be obtained from pharmaceutical companies through their medical representatives, meetings and drug advertisements in journals.
Formulary : It provides information about the available drugs in a country – their use, dose, dosage forms, adverse effects, contraindications, precautions, warnings and guidance on selecting the right drug for a range of conditions.
Drug nomenclature PH1.9
Drugs usually have three types of names, which are as follows:
- 1.
Chemical name: It denotes the chemical structure of a drug, e.g. acetylsalicylic acid is the chemical name of aspirin and N-acetyl-p-aminophenol is of paracetamol. It is not suitable for use in a prescription.
- 2.
Nonproprietary name: It is assigned by a competent scientific body/authority, e.g. the United States Adopted Name (USAN) council. WHO *
* S Kopp-Kubel. International Nonproprietary Names (INN) for pharmaceutical substances. Bull World Health Organ 1995;73(3):275–279.
along with its member countries select and recommend the International Nonproprietary Name (INN) for a drug. So, it is uniform throughout the world and denotes the active pharmaceutical ingredient. Few older drugs have more than one nonproprietary name, e.g. the opioid, pethidine and meperidine. The INN is commonly used as generic name. Ideally, generic names should be used in prescriptions because it is economical and generally uniform all over the world than the branded counterparts. Examples are aspirin and paracetamol are generic names. - 3.
Proprietary name (brand name): It is given by the drug manufacturers. Brand names are short and easy to recall. Drugs sold under brand name are expensive as compared to their generic version. A drug usually has many brand names – it may have different names within a country and in different countries. Brand names can also be used in prescriptions. Disprin is a brand name of aspirin; Crocin for paracetamol.
Chemical name Nonproprietary name Proprietary name/brand name Acetylsalicylic acid Aspirin - •
Disprin
- •
Ecosprin
N-acetyl-p-aminophenol
(Acetaminophen)Paracetamol - •
Crocin
- •
Metacin
- •
Tylenol
- •
Sources of drugs
They are natural, semisynthetic and synthetic. Natural sources are plants, animals, minerals, microorganisms, etc. Semisynthetic drugs are obtained from natural sources and are later chemically modified. Synthetic drugs are produced artificially.
The different sources of drugs:
- 1.
Plants:
- a.
Alkaloids are nitrogen containing compounds, e.g. morphine, atropine, quinine, reserpine, ephedrine.
- b.
Glycosides contain sugar group in combination with nonsugar through ether linkage, e.g. digoxin, digitoxin.
- c.
Volatile oils have aroma. They are useful for relieving pain (clove oil), as carminative (eucalyptus oil), flavouring agent (peppermint oil), etc.
- d.
Resins are sticky organic compounds obtained from plants as exudate, e.g. tincture benzoin (antiseptic).
- a.
- 2.
Animals: Insulin, heparin, antisera.
- 3.
Minerals: Ferrous sulphate, magnesium sulphate.
- 4.
Microorganisms: Penicillin G, streptomycin, griseofulvin (antimicrobial agents), streptokinase (fibrinolytic).
- 5.
Semisynthetic: Hydromorphone, hydrocodone.
- 6.
Synthetic: Most of the drugs used today are synthetic, e.g. aspirin, paracetamol.
Drugs are also produced by genetic engineering (DNA recombinant technology), e.g. human insulin, human growth hormone and hepatitis B vaccine.
Routes of drug administration PH1.11
Most of the drugs can be administered by different routes. Drug- and patient-related factors determine the selection of routes for drug administration. These factors are
- 1.
Characteristics of the drug.
- 2.
Emergency/routine use.
- 3.
Condition of the patient (unconscious, vomiting and diarrhoea).
- 4.
Age of the patient.
- 5.
Associated diseases.
- 6.
Patient’s/doctor’s choice (sometimes).
Local routes
It is the simplest mode of administration of a drug at the site where the desired action is required. Systemic side effects are minimal.
- 1.
Topical: Drug is applied to the skin or mucous membrane at various sites for localized action.
- a.
Oral cavity: As suspension, e.g. nystatin; as a troche, e.g. clotrimazole (for oral candidiasis); as a cream, e.g. acyclovir (for herpes labialis); as ointment, e.g. 5% lignocaine hydrochloride (for topical anaesthesia); as a spray, e.g. 10% lignocaine hydrochloride (for topical anaesthesia).
- b.
GI tract: As tablet which is not absorbed, e.g. neomycin (for sterilization of gut before surgery).
- c.
Rectum and anal canal:
- 1)
As an enema (administration of drug into the rectum in liquid form):
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Evacuant enema (for evacuation of bowel): For example, soap water enema – soap acts as a lubricant and water stimulates rectum.
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Retention enema: For example, methylprednisolone in ulcerative colitis.
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- 2)
As a suppository (administration of the drug in a solid form into the rectum), e.g. bisacodyl suppository for evacuation of bowel.
- 1)
- d.
Eye, ear and nose: As drops, ointment and spray (for infection, allergic conditions, etc.), e.g. gentamicin – eye and ear drops.
- e.
Bronchi: As inhalation, e.g. salbutamol, ipratropium bromide, etc. (for bronchial asthma and chronic obstructive pulmonary disease).
- f.
Vagina: As tablet, cream, pessary, etc. (for vaginal candidiasis).
- g.
Urethra: As jelly, e.g. lignocaine.
- h.
Skin: As ointment, cream, lotion, powder, e.g. clotrimazole (antifungal) for cutaneous candidiasis.
- a.
- 2.
Intra-arterial route: This route is rarely employed. It is mainly used during diagnostic studies, such as coronary angiography and for the administration of some anticancer drugs, e.g. for treatment of malignancy involving limbs.
- 3.
Administration of the drug into deep tissues by injection, e.g. administration of triamcinolone directly into the joint space in rheumatoid arthritis.
Systemic routes
Drugs administered by this route enter the blood and produce systemic effects.
Enteral routes
They include oral, sublingual and rectal routes.
Oral route.
It is the most common and acceptable route for drug administration. Dosage forms are tablet, capsule, powder, syrup, linctus, mixture, suspension, etc., e.g. paracetamol tablet for fever, omeprazole capsule for peptic ulcer are given orally. Tablets could be coated (covered with a thin film of another substance) or uncoated. They are also available as chewable (albendazole), dispersible (aspirin), mouth dissolving (ondansetron) and sustained release forms. Capsules have a soft or hard shell.
Advantages
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Safer.
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Cheaper.
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Painless.
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Convenient for repeated and prolonged use.
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Can be self-administered.
Disadvantages
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It is not suitable for/in:
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unpalatable and highly irritant drugs
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unabsorbable drugs (e.g. aminoglycosides)
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drugs that are destroyed by digestive juices (e.g. insulin)
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drugs with extensive first-pass metabolism (e.g. lignocaine)
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unconscious patients
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uncooperative and unreliable patients
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patients with severe vomiting and diarrhoea
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emergency as onset of action of orally administrated drugs is slow
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Sublingual route.
The preparation is kept under the tongue. The drug is absorbed through the buccal mucous membrane and enters systemic circulation directly, e.g. nitroglycerin(for acute attack of angina) and buprenorphine.
Advantages
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Quick onset of action of the drug.
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Action can be terminated by spitting out the tablet.
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Bypasses the first-pass metabolism.
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Self-administration is possible.
Disadvantages
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It is not suitable for:
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irritant and lipid-insoluble drugs
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drugs with bad taste
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Rectal route.
Drugs can be given in the form of solid or liquid.
- 1.
Suppository: It can be used for local (topical) effect (see p. 4) as well as systemic effect, e.g. indomethacin for rheumatoid arthritis.
- 2.
Enema: Retention enema can be used for local effect (see p. 4) as well as systemic effect. The drug is absorbed through rectal mucous membrane and produces systemic effect, e.g. diazepam for status epilepticus in children methylprednisolone enema in ulcerative colitis.
Parenteral routes
Routes of administration other than enteral route are called parenteral routes.
Advantages
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Onset of action of drugs is faster, hence suitable for emergency.
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Useful in:
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unconscious patient
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uncooperative and unreliable patient
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patients with vomiting and diarrhoea
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Suitable for:
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irritant drugs
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drugs with high first-pass metabolism
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drugs not absorbed orally
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drugs destroyed by digestive juices
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Disadvantages
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Require aseptic conditions.
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Preparation should be sterile, and is expensive.
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Require invasive techniques, which are painful.
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Cannot be usually self-administered.
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Can cause local tissue injury to nerves, vessels, etc.
Inhalation.
Volatile liquids and gases are given by inhalation for systemic effects, e.g. general anaesthetics.
Advantages
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Quick onset of action.
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Dose required is very less, so systemic toxicity is minimized.
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Amount of drug administered can be regulated.
Disadvantages
- ■
Local irritation may cause increased respiratory secretion and bronchospasm.
Injections ( fig. 1.1 )
Intradermal route.
The drug is injected into the layers of skin, e.g. BCG vaccination and drug sensitivity tests. It is painful and a small amount of the drug can be administered.
Subcutaneous (s.c.) route.
The drug is injected into the subcutaneous tissue of the thigh, abdomen, arm, e.g. adrenaline, insulin, etc.
Advantages
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Self-administration of drug is possible, e.g. insulin.
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Depot preparations can be inserted into the subcutaneous tissue, e.g. norplant for contraception.
Disadvantages
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It is suitable only for nonirritant drugs.
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Drug absorption is slow, hence not suitable for emergency.
Intramuscular (i.m.) route.
Drugs are injected into large muscles, such as deltoid, gluteus maximus and vastus lateralis, e.g. paracetamol, diclofenac, etc. A volume of 5–10 mL can be given at a time.
Advantages
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Absorption is more rapid as compared to oral route.
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Mild irritants, depot injections, soluble substances and suspensions can be given by this route.
Disadvantages
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Aseptic conditions are needed.
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Intramuscular (i.m.) injections are painful and may cause abscess.
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Self-administration is not possible.
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There may be injury to nerves.
Intravenous (i.v.) route.
Drugs are injected directly into the blood stream through a vein. Drugs are administered as
- 1.
Bolus: Single, relatively large dose of a drug injected rapidly or slowly into a vein, e.g. i.v. ranitidine in bleeding peptic ulcer.
- 2.
Slow intravenous injection: For example, i.v. morphine in myocardial infarction.
- 3.
Intravenous infusion: For example, dopamine infusion in cardiogenic shock; mannitol infusion in cerebral oedema; fluids infused intravenously in dehydration.
Advantages
- ■
Bioavailability is 100%.
- ■
Quick onset of action, so it is the route of choice in emergency, e.g. intravenous diazepam to control convulsions in status epilepticus.
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Large volume of fluid can be administered, e.g. intravenous fluids in patients with severe dehydration.
- ■
Highly irritant drugs, e.g. anticancer drugs can be given because they get diluted in blood.
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Hypertonic solution can be infused by intravenous route, e.g. 20% mannitol in cerebral oedema.
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By i.v. infusion, a constant plasma level of the drug can be maintained, e.g. dopamine infusion in cardiogenic shock.
Disadvantages
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Local irritation may cause phlebitis.
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Self-administration is usually not possible.
- ■
Strict aseptic conditions are needed.
- ■
Extravasation of some drugs (e.g. noradrenaline) can cause injury, necrosis and sloughing of tissues.
- ■
Depot preparations cannot be given by i.v. route.
Precautions
- ■
Drug should usually be injected slowly.
- ■
Before injecting, make sure that the tip of the needle is in the vein.
Intrathecal route.
Drug is injected into the subarachnoid space, e.g. lignocaine (spinal anaesthesia), antibiotics (amphotericin B), etc.
Transdermal route (transdermal therapeutic system).
The drug is administered in the form of a patch or ointment that delivers the drug into the circulation for systemic effect ( Fig. 1.2 ), e.g. scopolamine patch for sialorrhoea and motion sickness, nitroglycerin patch/ointment for prophylaxis of angina, oestrogen patch for hormone replacement therapy (HRT), clonidine patch for hypertension, fentanyl patch for terminal stages of cancer pain and chronic pain, nicotine patch for tobacco deaddiction, etc.
Advantages
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Self-administration is possible.
- ■
Patient compliance is better.
- ■
Duration of action is prolonged.
- ■
Systemic side effects are reduced.
- ■
Provides a constant plasma concentration of the drug.
- ■
First-pass metabolism is bypassed.
Disadvantages
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Expensive.
- ■
Local irritation may cause dermatitis and itching.
- ■
Patch may fall off unnoticed.
Special drug delivery systems PH1.3
They have been developed to prolong duration of drug action, for targeted delivery of drugs or to improve patient compliance.
- 1.
Ocusert: It is kept beneath the lower eyelid in glaucoma. It releases the drug slowly for a week following a single application, e.g. pilocarpine ocusert.
- 2.
Progestasert: It is an intrauterine contraceptive device that releases progesterone slowly for a period of one year.
- 3.
Liposomes: They are minute vesicles made of phospholipids into which the drug is incorporated. They help in targeted delivery of drugs, e.g. liposomal formulation of amphotericin B for fungal infections.
- 4.
Monoclonal antibodies: They are immunoglobulins, produced by cell culture, selected to react with a specific antigen. They are useful for targeted delivery of drugs, e.g. delivery of anticancer drugs using monoclonal antibodies.
- 5.
Drug-eluting stents: e.g. paclitaxel releasing stents used in coronary angioplasty.
- 6.
Computerized, miniature pumps, e.g. insulin pump for continuous subcutaneous delivery of insulin
Pharmacokinetics PH1.4
Pharmacokinetics is derived from two words: Pharmacon meaning drug and kinesis meaning movement. In short, it is ‘what the body does to the drug’. It includes absorption (A), distribution (D), metabolism (M) and excretion (E). All these processes involve movement of the drug molecule through various biological membranes.
All biological membranes are made up of a lipid bilayer. Drugs cross various biological membranes by the following mechanisms:
- 1.
Passive diffusion: It is a bidirectional process. The drug molecules move from a region of higher to lower concentration until equilibrium is attained. The rate of diffusion is directly proportional to the concentration gradient across the membrane. Lipid-soluble drugs are transported across the membrane by passive diffusion. It does not require energy and is the process by which majority of the drugs are absorbed.
- 2.
Active transport: Drug molecules move from a region of lower to higher concentration against the concentration gradient. It requires energy, e.g. transport of sympathomimetic amines into neural tissue, transport of choline into cholinergic neurons and absorption of levodopa from the intestine. In primary active transport, energy is obtained by hydrolysis of ATP. In secondary active transport, energy is derived from transport of another substrate (either symport or antiport).
- 3.
Facilitated diffusion: This is a type of carrier-mediated transport and does not require energy. The drug attaches to a carrier in the membrane, which facilitates its diffusion across the membrane. The transport of molecules is from the region of higher to lower concentration, e.g. transport of glucose across muscle cell membrane by a transporter GLUT 4.
- 4.
Filtration: Filtration depends on the molecular size and weight of the drug. If drug molecules are smaller than the pores, they are filtered easily through the membrane.
- 5.
Endocytosis: The drug is taken up by the cell through vesicle formation. Absorption of vitamin B 12 –intrinsic factor complex in the gut is by endocytosis.
Drug absorption PH1.4
Movement of a drug from the site of administration into the blood stream is known as absorption.
Factors influencing drug absorption
- 1.
Physicochemical properties of the drug:
- a.
Physical state: Liquid form of the drug is better absorbed than solid formulations.
- b.
Lipid-soluble and unionized form of the drug is better absorbed than water-soluble and ionized form.
- c.
Particle size: Drugs with smaller particle size are absorbed better than larger ones, e.g. microfine aspirin, digoxin and griseofulvin are well absorbed from the gut and produce better effects. Some of the anthelmintics have larger particle size. They are poorly absorbed through gastrointestinal (GI) tract, hence they produce better effect on gut helminths.
- d.
Disintegration time: It is the time taken for the formulation (tablet or capsule) to break up into small particles and its variation may affect the bioavailability.
- e.
Dissolution time: It is the time taken for the particles to go into solution. Shorter the time, better is the absorption.
- f.
Formulations: Pharmacologically inert substances like lactose, starch, calcium sulphate, gum, etc. are added to formulations as binding agents. These are not totally inert and may affect the absorption of drugs, e.g. calcium reduces the absorption of tetracyclines.
- a.
- 2.
Route of drug administration: A drug administered by intravenous route bypasses the process of absorption as it directly enters the circulation. Some drugs are highly polar compounds, ionize in solution and are not absorbed through GI tract, hence are given parenterally, e.g. gentamicin. Drugs like insulin are administered parenterally because they are degraded in the GI tract on oral administration.
- 3.
pH and ionization: Strongly acidic (heparin) and strongly basic (aminoglycosides) drugs usually remain ionized at all pH, hence they are poorly absorbed ( Fig. 1.3 ).
Fig. 1.3 Effect of pH and ionization on drug absorption. - 4.
Food: Presence of food in the stomach can affect the absorption of some drugs. Food decreases the absorption of rifampicin, levodopa, etc., hence they should be taken on an empty stomach for better effect. Milk and milk products decrease the absorption of tetracyclines. Fatty meal increases the absorption of griseofulvin.
- 5.
Presence of other drugs: Concurrent administration of two or more drugs may affect their absorption, e.g. ascorbic acid increases the absorption of oral iron. Antacids reduce the absorption of tetracyclines.
- 6.
Area of the absorbing surface: Normally, drugs are better absorbed in small intestine because of a larger surface area. Resection of the gut decreases absorption of drugs due to a reduced surface area.
- 7.
Gastrointestinal and other diseases: In gastroenteritis, there is increased peristaltic movement that decreases drug absorption. In achlorhydria, absorption of iron from the gut is reduced. In congestive cardiac failure, there is GI mucosal oedema that reduces absorption of drugs.
Bioavailability
It is the fraction of a drug that reaches systemic circulation from a given dose. Intravenous route of drug administration gives 100% bioavailability as it directly enters the circulation. The term bioavailability is used commonly for drugs given by oral route.
If two formulations of the same drug produce equal bioavailability, they are said to be bioequivalent. If formulations differ in their bioavailability, they are said to be bioinequivalent.
Factors affecting bioavailability.
The factors which affect drug absorption (physicochemical properties of the drug, route of drug administration, pH and ionization, food, presence of other drugs, area of absorbing surface, GI and other diseases) also affect bioavailability of a drug . Other factors that affect the bioavailability of a drug are discussed as follows:
- 1.
First-pass metabolism (First-pass effect, presystemic elimination): When drugs are administered orally, they have to pass via gut wall → portal vein → liver → systemic circulation ( Fig. 1.4 ). During this passage, certain drugs get metabolized and are removed or inactivated before they reach the systemic circulation. This process is known as first-pass metabolism. The net result is a decreased bioavailability of the drug and diminished therapeutic response, e.g. drugs like lignocaine (liver), isoprenaline (gut wall), etc.
Consequences of high first-pass metabolism:
- 1)
Drugs which undergo extensive first-pass metabolism are administered parenterally, e.g. lignocaine is administered intravenously in ventricular arrhythmias.
- 2)
Dose of a drug required for oral administration is more than that given by other systemic routes, e.g. nitroglycerin.
- 1)
Fig. 1.4 First-pass metabolism. - 2.
Hepatic diseases: They result in a decrease in drug metabolism, thus increasing the bioavailability of drugs that undergo high first-pass metabolism, e.g. propranolol and lignocaine.
- 3.
Enterohepatic cycling: Some drugs are excreted via bile but after reaching the intestine they are reabsorbed → liver → bile → intestine and the cycle is repeated – such recycling is called enterohepatic circulation and it increases bioavailability as well as the duration of action of the drug, e.g. morphine and doxycycline.
Drug distribution PH1.4
Distribution is defined as the reversible transfer of drugs between body-fluid compartments. After absorption, a drug enters the systemic circulation and is distributed in the body fluids. Various body-fluid compartments for a 70-kg person can be depicted as follows:
Apparent volume of distribution
Apparent volume of distribution (a V d ) is defined as the hypothetical volume of body fluid into which a drug is uniformly distributed at a concentration equal to that in plasma, assuming the body to be a single compartment.
- ■
Drugs with high molecular weight (e.g. heparin) or extensively bound to plasma protein (e.g. warfarin) are largely restricted to the vascular compartment, hence their a V d is low.
- ■
If a V d of a drug is about 14–16 L (0.25 mL/kg in a person weighing 70 kg), it indicates that the drug is distributed in the ECF, e.g. gentamicin, streptomycin, etc.
- ■
Small water-soluble molecules like ethanol are distributed in total body water – a V d is approximately 42 L.
- ■
Drugs which accumulate in tissues have a volume of distribution which exceeds total body water, e.g. chloroquine (13,000 L) and digoxin (500 L). Haemodialysis is not useful for removal of drugs with large a V d in case of overdosage.
- ■
In congestive cardiac failure, V d of some drugs can increase due to an increase in ECF volume (e.g. alcohol) or decrease because of reduced perfusion of tissues.
- ■
In uraemia, the total body water can increase which increases V d of small water-soluble drugs. Toxins which accumulate can displace drugs from plasma protein binding sites resulting in increased concentration of free form of drug which can leave the vascular compartment leading to an increase in V d.
- ■
Fat:lean body mass ratio – highly lipid-soluble drugs get distributed to the adipose tissue. If the ratio is high, the volume of distribution for such a drug will be higher; fat acts as a reservoir for such drugs.
Redistribution (see p. 178)
Highly lipid-soluble drug, such as thiopentone, on intravenous administration, immediately gets distributed to the areas of high blood flow, such as brain, and causes general anaesthesia. Immediately within few minutes, it diffuses across the blood–brain barrier (BBB) into blood and then to the less perfused tissues, such as muscle and adipose tissue. This is called redistribution, which results in termination of drug action. Thiopentone has a very short duration of action (5–10 minutes) and is used for induction of general anaesthesia.
Drug reservoirs or tissue storage
Some drugs are concentrated or accumulated in tissues or some organs of the body, which can lead to toxicity on chronic use, e.g. tetracyclines – bones and teeth; thiopentone and DDT – adipose tissue; chloroquine – liver and retina; digoxin – heart, etc.
Blood–brain barrier
The capillary boundary that is present between blood and brain is called blood—brain barrier (BBB). In the brain capillaries, the endothelial cells are joined by tight junctions. Only the lipid-soluble and unionized form of drugs can pass through BBB and reach the brain, e.g. barbiturates, diazepam, volatile anaesthetics, amphetamine, etc. Lipid-insoluble and ionized particles do not cross the BBB, e.g. dopamine and aminoglycosides.
Pathological states like meningitis and encephalitis increase the permeability of the BBB and allow the normally impermeable substances to enter the brain, e.g. penicillin G in normal conditions has poor penetration through BBB, but its penetrability increases during meningitis and encephalitis.
Placental barrier
Drugs administered to a pregnant woman can cross placenta and reach the fetus. Passage across placenta is affected by lipid solubility, degree of plasma protein binding, presence of transporters, etc. Quaternary ammonium compounds, e.g. d-tubocurarine (d-TC) and substances with high molecular weight like insulin cannot cross the placental barrier.
Plasma protein binding PH1.4
Many drugs bind to plasma proteins like albumin, α 1 acid glycoprotein, etc.
Clinical importance of plasma protein binding
- 1.
- 2.
Drugs that are highly bound to plasma proteins have a low volume of distribution .
- 3.
Plasma protein binding delays the metabolism of drugs.
- 4.
Bound form is not available for filtration at the glomeruli. Hence, excretion of highly plasma protein bound drugs by filtration is delayed.
- 5.
Highly protein bound drugs have a longer duration of action, e.g. sulphadiazine is less plasma protein bound and has a duration of action of 6 hours, whereas sulphadoxine is highly plasma protein bound and has a duration of action of 1 week.
- 6.
In case of poisoning, highly plasma protein bound drugs are difficult to be removed by haemodialysis.
- 7.
In disease states like anaemia, renal failure, chronic liver diseases, etc. plasma albumin levels are low (hypoalbuminaemia). So, there will be a decrease in bound form and an increase in free form of the drug, which can lead to drug toxicity.
- 8.
Plasma protein binding can cause displacement interactions. More than one drug can bind to the same site on plasma protein. The drug with higher affinity will displace the one having lower affinity and may result in a sudden increase in the free concentration of the drug with lower affinity.
Biotransformation (drug metabolism) PH1.4
Chemical alteration of the drug in a living organism is called biotransformation. The metabolism of a drug usually converts lipid-soluble and unionized compounds into water-soluble and ionized compounds, hence not reabsorbed in the renal tubules and are excreted. If the parent drug is highly polar (ionized), then it may not get metabolized and is excreted as such.
Sites: Liver is the main site for drug metabolism; other sites are GI tract, kidney, lungs, blood, skin and placenta.
The end result of drug metabolism is inactivation, but sometimes a compound with pharmacological activity may be formed as shown below:
- 1.
Active drug to inactive metabolite : This is the most common type of metabolic transformation.
Phenobarbitone
Hydroxyphenobarbitone
Phenytoin
p -Hydroxyphenytoin
- 2.
Active drug to active metabolite
Codeine
Morphine
Diazepam
Oxazepam
- 3.
Inactive drug (prodrug) to active metabolite
Levodopa
Dopamine
Prednisone
Prednisolone
Prodrug
It is an inactive form of a drug, which is converted to an active form after metabolism.
Uses of prodrugs (advantages)
- 1.
To improve bioavailability: Parkinsonism is due to deficiency of dopamine. Dopamine itself cannot be used since it does not cross BBB. So, it is given in the form of a prodrug, levodopa. Levodopa crosses the BBB and is then converted into dopamine.
- 2.
To prolong the duration of action: Phenothiazines have a short duration of action, whereas esters of phenothiazine (fluphenazine) have a longer duration of action.
- 3.
To improve taste: Clindamycin has a bitter taste, so clindamycin palmitate suspension has been developed for paediatric use to improve the taste.
- 4.
To provide site-specific drug delivery:
Pathways of drug metabolism.
Drug metabolic reactions are grouped into two phases. They are Phase I or nonsynthetic reactions and Phase II or synthetic reactions.
Phase I reactions ( table 1.1 ).
Oxidation: Addition of oxygen or removal of hydrogen is called oxidation. It is the most important and common metabolic reaction.
- ■
Oxidation reactions are mainly carried out by cytochrome P450, cytochrome P450 reductase, molecular O 2 and NADPH.
- ■
There are several cytochrome P450 isoenzymes.
- ■
They are numbered as 1,2,3,4... (to denote families) and each as A, B, C, D (subfamilies).
- ■
More than 50% of drugs undergo biotransformation reactions by CYP3A4/5. Other enzymes include CYP2D6, CYP2C9, CYP2E1, CYP2C19, etc.
| Oxidation | Addition of oxygen/removal of hydrogen | Phenytoin, phenobarbitone, pentobarbitone, propranolol |
| Reduction | Removal of oxygen/addition of hydrogen | Chloramphenicol, methadone |
| Hydrolysis | Break down of compound by addition of water | Esters – procaine, succinylcholine Amides – lignocaine, procainamide |
| Cyclization | Conversion of straight chain compound into ring structure | Proguanil |
| Decyclization | Breaking up of the ring structure of the drug | Phenobarbitone, phenytoin |
Reduction: Removal of oxygen or addition of hydrogen is known as reduction.
Hydrolysis: Breakdown of the compound by addition of water is called hydrolysis. This is common among esters and amides.
Cyclization: Conversion of a straight chain compound into ring structure.
Decyclization: Breaking up of the ring structure of the drug.
At the end of phase I, the metabolite may be active or inactive.
Phase II reactions ( table 1.2 ).
Phase II consists of conjugation reactions. If the phase I metabolite is polar, it is excreted in urine or bile. However, many metabolites are lipophilic and undergo subsequent conjugation with an endogenous substrate, such as glucuronic acid, sulphuric acid, acetic acid or amino acid. These conjugates are polar, usually water-soluble and inactive.
| Conjugation reaction | Enzyme | Examples |
| Glucuronidation | UDP glucuronosyl transferase |
|
| Acetylation | N-acetyltransferase |
|
| Sulphation | Sulphotransferase |
|
| Methylation | Transmethylase |
|
| Glutathione conjugation | Glutathione transferase |
|
| Glycine conjugation | Acyl CoA glycine transferase |
|
Not all drugs undergo phase I and phase II reactions in that order. In case of isoniazid (INH), phase II reaction precedes phase I reaction ( Fig. 1.5 ).
Drug-metabolizing enzymes
They are broadly divided into two groups – microsomal and nonmicrosomal enzyme systems ( Table 1.3 ).
| Microsomal enzymes | Nonmicrosomal enzymes |
| Location | |
| Smooth endoplasmic reticulum of cells, liver, kidney, lungs, e.g. cytochrome P450, monooxygenase, glucuronyl transferase | Cytoplasm, mitochondria, plasma, e.g. conjugases, esterases, amidases, flavoprotein oxidases |
| Reactions | |
| Most of the phase I reactions, Glucuronide conjugation | Oxidation, reduction (few), hydrolysis. All conjugations except glucuronide conjugation |
| Inducible | Not inducible – may show genetic polymorphism |
Hofmann elimination
Drugs can be inactivated without the need of enzymes – this is known as Hofmann elimination. Atracurium, a skeletal muscle relaxant, undergoes Hofmann elimination.
Factors affecting drug metabolism
- 1.
Age: Neonates and elderly metabolize some drugs to a lesser extent than adults. In these cases, it is due to diminished amount/activity of hepatic microsomal enzymes. Neonates conjugate chloramphenicol more slowly, hence develop toxicity – grey baby syndrome. Increased incidence of toxicity with propranolol and lignocaine in elderly is due to their decreased hepatic metabolism.
- 2.
Diet: Poor nutrition can decrease enzyme function.
- 3.
Diseases: Chronic diseases of liver may affect hepatic metabolism of some drugs, e.g. increased duration of action of diazepam, in patients with cirrhosis, due to its impaired metabolism.
- 4.
Genetic factors (pharmacogenetics): These factors also influence drug metabolism. The study of genetically determined variation in drug response is called pharmacogenetics
- a.
Slow and fast acetylators of isoniazid: There is an increased incidence of peripheral neuritis with isoniazid in slow acetylators. The fast acetylators require a larger dose of the drug to produce therapeutic effect.
- b.
Succinylcholine apnoea: Succinylcholine, a neuromuscular blocker, is metabolized by plasma pseudocholinesterase enzyme. The duration of action of succinylcholine is 3–6 minutes. However, some individuals have atypical pseudocholinesterase that metabolizes the drug very slowly. This results in prolonged succinylcholine apnoea due to paralysis of respiratory muscles, which is dangerous.
- c.
Glucose-6-phosphate dehydrogenase (G6PD) deficiency and haemolytic anaemia: G6PD activity is important to maintain the integrity of the RBCs. A person with G6PD deficiency may develop haemolysis when exposed to certain drugs like sulphonamides, primaquine, salicylates, dapsone, etc.
- a.
- 5.
Simultaneous administration of drugs: This can result in increased or decreased metabolism of drugs (see enzyme induction or inhibition).
Enzyme induction.
Repeated administration of certain drugs increases the synthesis of microsomal enzymes. This is known as enzyme induction. The drug is referred to as an enzyme inducer, e.g. rifampicin, phenytoin, barbiturates, carbamazepine, griseofulvin, etc.
Clinical importance of microsomal enzyme induction
- 1.
Enzyme induction may accelerate the metabolism of drugs, thus reducing the duration and intensity of drug action leading to therapeutic failure, e.g. rifampicin and oral contraceptives. Rifampicin induces the drug metabolizing enzyme of oral contraceptives, thus enhancing its metabolism and leading to contraceptive failure.
- 2.
Autoinduction may lead to development of drug tolerance, e.g. carbamazepine enhances its own metabolism.
- 3.
Enzyme induction can lead to drug toxicity, e.g. increased incidence of hepatotoxicity with paracetamol in alcoholics is due to overproduction of toxic metabolite of paracetamol.
- 4.
Prolonged phenytoin therapy may produce osteomalacia due to enhanced metabolism of vitamin D 3 .
- 5.
Enzyme inducers, e.g. barbiturates, can precipitate porphyria due to overproduction of porphobilinogen.
- 6.
Enzyme induction can also be beneficial, e.g. phenobarbitone in neonatal jaundice – phenobarbitone induces glucuronyl transferase enzyme, hence bilirubin is conjugated and jaundice is resolved.
Enzyme inhibition.
Certain drugs, e.g. chloramphenicol, ciprofloxacin, erythromycin, etc. inhibit the activity of drug metabolizing enzymes and are known as enzyme inhibitors. Inhibition of metabolism of one drug by another can occur when both are metabolized by the same enzyme. Enzyme inhibition is a rapid process as compared to enzyme induction.
Clinical relevance of enzyme inhibition.
Enzyme inhibition can result in drug toxicity, e.g. increased incidence of bleeding with warfarin, due to concomitant administration of erythromycin or chloramphenicol, etc. These drugs inhibit drug metabolizing enzyme of warfarin resulting in increased plasma concentration of warfarin and enhanced anticoagulant effect (bleeding). Toxicity following inhibition of metabolism is significant for those drugs which have saturation kinetics of metabolism. Enzyme inhibition can be beneficial, e.g. boosted protease inhibitor regimen used for treatment of HIV infection (see p. 436).
Drug excretion PH1.4
Removal of the drug and its metabolite from the body is known as drug excretion. The main channel of excretion of drugs is the kidney; others include lungs, bile, faeces, sweat, saliva, tears, milk, etc.
- 1.
Kidney: The processes involved in the excretion of drugs via kidney are glomerular filtration, passive tubular reabsorption and active tubular secretion. Glomerular filtration and active tubular secretion facilitate drug excretion, whereas tubular reabsorption decreases drug excretion.
Rate of renal excretion = (Rate of filtration + Rate of secretion) – Rate of reabsorption
- 1)
Glomerular filtration: Drugs with small molecular size are more readily filtered. The extent of filtration is directly proportional to the glomerular filtration rate (GFR) and to the fraction of the unbound drug in plasma.
- 2)
Passive tubular reabsorption: The main factor affecting passive reabsorption is the pH of renal tubular fluid and the degree of ionization. Strongly acidic and strongly basic drugs remain in ionized form at any pH of urine, hence are excreted in urine.
- a)
Weakly acidic drugs (e.g. salicylates, barbiturates) in acidic urine remain mainly in ‘unionized’ form, so they are reabsorbed into the circulation. If the pH of urine is made alkaline by sodium bicarbonate, the weakly acidic drugs get ‘ionized’ and are excreted easily.
- b)
Similarly, weakly basic drugs (e.g. morphine, amphetamine, etc.) in alkaline urine remain in ‘unionized’ form, hence are reabsorbed. If the pH of urine is made acidic by vitamin C (ascorbic acid), these weakly basic drugs get ‘ionized’ and are excreted easily.
- a)
- 3)
Active tubular secretion: It is a carrier-mediated active transport which requires energy. Active secretion is unaffected by changes in the pH of urine and protein binding. Most of the acidic drugs (e.g. penicillin, diuretics, probenecid, sulphonamides, etc.) and basic drugs (e.g. quinine, procaine, morphine, etc.) are secreted by the renal tubular cells. The carrier system is relatively nonselective and therefore drugs having similar physicochemical properties compete for the same carrier system, e.g. probenecid competitively inhibits the tubular secretion of penicillins, thereby increasing the duration of action as well as the plasma half-life and effectiveness of penicillins in the treatment of diseases, such as gonococcal infections.
- 1)
- 2.
Lungs: Alcohol and volatile general anaesthetics, such as ether, halothane, isoflurane, sevoflurane and ether are excreted via lungs.
- 3.
Faeces: Drugs like purgatives, e.g. senna, cascara, etc. are excreted in faeces
- 4.
Bile: Some drugs are secreted in bile. They are reabsorbed in the gut while a small portion is excreted in faeces, e.g. tetracyclines.
- 5.
Skin: Metals like arsenic and mercury are excreted through skin.
- 6.
Saliva: Certain drugs like potassium iodide, phenytoin, metronidazole and lithium are excreted in saliva. Salivary estimation of lithium may be used for noninvasive monitoring of lithium therapy.
- 7.
Milk: Drugs taken by lactating women may appear in milk. They may or may not adversely affect the breast fed infant. Drugs like penicillins, erythromycin, etc. are safe for use but amiodarone is to be avoided in mothers during breast feeding.
Pharmacokinetic parameters
The important pharmacokinetic parameters are bioavailability, volume of distribution, plasma half-life (t 1/2 ) and clearance.
Plasma half-life (t 1/2 )
It is the time required for the plasma concentration of a drug to decrease by 50% of its original value ( Fig. 1.6 A). Plasma half-life of lignocaine is 1 hour and for aspirin it is 4 hours.
Clinical importance of plasma half-life.
It helps to
- ■
determine the duration of drug action.
- ■
determine the frequency of drug administration.
- ■
estimate the time required to reach the steady state. At steady state, the amount of drug administered is equal to the amount of drug eliminated in the dose interval. It takes approximately four to five half-lives to reach the steady state during repeated administration of the drug. A drug is almost completely eliminated in four to five half-lives after single administration.
Clearance
Clearance (CL) of a drug is defined as that volume of plasma from which the drug is removed in unit time.
- 1.
First-order kinetics: A constant f raction of the drug in the body is eliminated per unit time.
For example, assume drug ‘A’ with plasma t 1/2 of 1 hour following first-order kinetics of elimination and having an initial plasma concentration of 100 mcg/mL.
If its concentration is increased to 200 mcg/mL, a constant fraction (1/2) gets eliminated in unit time, i.e. after 1 hour, concentration is 100 mcg/mL.
The rate of drug elimination is directly proportional to its plasma concentration. The t 1/2 of the drugs following first-order kinetics will always remain constant. The drug will be almost completely eliminated in four to five plasma half-lives if administered at a constant rate at each half-life. Most of the drugs follow first-order kinetics.
- 2.
Zero-order kinetics: A constant amount of a drug in the body is eliminated per unit time. For example, ethanol is eliminated from the body at the rate of about 10 mL/h.
Assume a drug ‘B’ with an initial plasma concentration of 200 mcg/mL and eliminated at a constant amount of 10 mcg per unit time. The concentration will be 190 mcg/mL after 1 hour and 100 mcg/mL after 10 hours. So, half-life is 10 hours.
If its concentration is increased to 300 mcg/mL, concentration will be 290 mcg/mL after 1 hour (as constant amount 10 mcg per unit time is eliminated) and 150 mcg/mL after 15 hours. The half-life increases to 15 hours. Thus, the t 1/2 of the drug following zero-order kinetics is never constant. The rate of elimination is independent of plasma drug concentration
Note: Phenytoin exhibits saturation kinetics and its plasma concentration has to be carefully monitored (therapeutic drug monitoring, TDM) when used in the treatment of epilepsy. Once the kinetics changes to zero order, an increase in dose will result in a marked increase in plasma concentration leading to drug toxicity.
Steady-state concentration
If constant dose of a drug is given at constant intervals at its t 1/2 , plasma concentration of the drug increases due to its absorption and falls due to elimination in each dosing interval. Finally, the amount of drug eliminated will equal the amount of drug administered in the dosing interval. The drug is said to have reached steady-state or plateau level ( Fig. 1.6 B). It is attained after approximately four to five half-lives.
Target level strategy
The dosage of drug is calculated to achieve the desired plasma steady state concentration of the drug which produces therapeutic effect with minimal side effects.
Loading dose: Initially, a large dose or series of doses of a drug is given with the aim of rapidly attaining the target level in plasma. This is known as loading dose. A loading dose is administered if the time taken to reach steady state is relatively more as compared to the patient’s condition, e.g. the half-life of lignocaine is more than 1 hour, so it takes more than 4–6 hours to reach the target concentration at steady state. When a patient has life-threatening ventricular arrhythmias after myocardial infarction, initially a large dose of lignocaine has to be given to achieve desired plasma concentration quickly. Once it is achieved, it is maintained by giving the drug as an intravenous infusion.
Maintenance dose: The dose of a drug which is repeated at fixed intervals or given as a continuous infusion to maintain target level in plasma or steady-state concentration is known as maintenance dose. The dose administered is equal to dose eliminated in a dosing interval.
Therapeutic drug monitoring PH1.2
Monitoring drug therapy by measuring plasma concentration of a drug is known as therapeutic drug monitoring (TDM).
Indications of TDM
- 1.
Drugs with narrow therapeutic index, e.g. lithium, digoxin, phenytoin, aminoglycosides, etc.
- 2.
Drugs showing wide interindividual variations, e.g. tricyclic antidepressants.
- 3.
To ascertain patient compliance.
- 4.
For drugs whose toxicity is increased in the presence of renal failure, e.g. aminoglycosides.
- 5.
In patients who do not respond to therapy without any known reason.
In drug poisoning, estimation of plasma drug concentration is done.
TDM is not required in the following situations:
- 1.
When clinical and biochemical parameters are available to assess response:
- a.
Blood pressure measurement for antihypertensives.
- b.
Blood sugar estimation for antidiabetic agents.
- c.
Prothrombin time, aPTT and International Normalized Ratio (INR) for anticoagulants.
- a.
- 2.
Drugs producing tolerance, e.g. opioids.
- 3.
Drugs whose effect persists longer than the drug itself, e.g. omeprazole.
Fixed-dose combinations (FDCs; fixed-dose ratio combinations) PH1.59
It is the combination of two or more drugs in a fixed-dose ratio in a single formulation.
Some of the examples of WHO approved FDCs are
- ■
Levodopa + carbidopa for parkinsonism
- ■
Isoniazid + rifampicin + pyrazinamide + ethambutol for tuberculosis.
- ■
Ferrous sulphate + folic acid for anaemia of pregnancy
- ■
Sulphamethoxazole + trimethoprim in cotrimoxazole (antimicrobial agent)
- ■
Amoxicillin + clavulanic acid (antimicrobial agent)
- ■
Oestrogen + progesterone (oral contraceptive)
Advantages and disadvantages of FDCs are explained in Table 1.4, p. 22.
| Advantages | Disadvantages |
|---|---|
|
|
Methods to prolong the duration of drug action
Prolongation of action of a drug helps
- ■
to reduce the frequency of drug administration.
- ■
to improve patient compliance.
- ■
to minimize fluctuations in plasma concentration.
Various methods to prolong the duration of drug action are
- 1.
By retarding drug absorption:
- a.
For orally administered drugs:
- ■
Using sustained release/controlled release preparations: Sustained release preparations consist of drug particles, which have different coatings that dissolve at different intervals of time. It prolongs the duration of action of the drug, reduces the frequency of administration and improves patient compliance, e.g. tab. diclofenac has a duration of action of 12 hours, whereas diclofenac sustained release preparation has a duration of action of 24 hours.
- ■
- b.
For parenterally administered drugs:
- ■
By decreasing the vascularity of the absorbing surface: This is achieved by adding a vasoconstrictor to the drug, e.g. adrenaline with local anaesthetics. When adrenaline is added to a local anaesthetic, the vasoconstriction produced by adrenaline will delay the removal of the local anaesthetic from the site of administration and prolongs the duration of its action. It also reduces the systemic toxicity of the local anaesthetic and minimizes bleeding in the operative field.
- ■
By decreasing the solubility of the drug: by combining it with a water-insoluble compound, e.g. combining procaine/benzathine with penicillin G.
- ■
Injection penicillin G has a duration of action of 4–6 hours.
- ■
Injection procaine penicillin G: It has a duration of action of 12–24 hours.
- ■
Injection benzathine penicillin G: It has a duration of action of 3–4 weeks.
- ■
- ■
By combining the drug with a protein , e.g. protamine zinc insulin – the complexed insulin is released slowly from the site of administration, thus prolonging its action.
- ■
By esterification: Esters of testosterone, e.g. testosterone propionate and testosterone enanthate are slowly absorbed following intramuscular administration resulting in prolonged action.
- ■
Injecting the drug in oily solution, e.g. depot progestins (depot medroxyprogesterone acetate).
- ■
Pellet implantation: e.g. norplant for contraception.
- ■
Transdermal patch (see p. 7)
- ■
- a.
- 2.
By increasing the plasma protein binding of the drug , e.g. sulphadiazine is less bound to plasma proteins and has duration of action of 6 hours. Sulphadoxine is highly protein bound and so has duration of action of 1 week.
- 3.
By inhibiting drug metabolism: For example, allopurinol + 6-mercaptopurine (6-MP). 6-MP is metabolized by xanthine oxidase. Allopurinol (xanthine oxidase inhibitor) → inhibits metabolism of 6-MP → prolongs action of 6-MP.
- 4.
By delaying renal excretion of the drug, e.g. penicillin/cephalosporins with probenecid (see p. 36).
Pharmacodynamics
Pharmacodynamics (Greek pharmacon: drug; dynamis: power). It covers all aspects relating to ‘what the drug does to the body’. It is the study of drugs – their mechanism of action, pharmacological actions and adverse effects.
Types of effects of a drug
- 1.
Stimulation: Some drugs act by increasing the activity of specific organ/system, e.g. adrenaline stimulates the heart resulting in an increase in heart rate and force of contraction.
- 2.
Depression: Some drugs act by decreasing the activity of specific organ/system, e.g. alcohol, barbiturates, general anaesthetics, etc. depress the central nervous system.
- 3.
Irritation: Certain agents on topical application can cause irritation of the skin and adjacent tissues. When an agent on application to the skin relieves deep seated pain, it is known as counterirritant, e.g. eucalyptus oil, methyl salicylate, etc. They are useful in sprain, joint pain and myalgia. They exert their action by
- ■
reflexly increasing local circulation in deeper structures.
- ■
blocking impulse conduction in the spinal cord.
- ■
- 4.
Cytotoxic: Drugs are selectively toxic for the infecting organism/cancer cells, e.g. antibiotics/anticancer drugs.
- 5.
Replacement: When there is a deficiency of endogenous substances, they can be replaced by drugs, e.g. insulin in diabetes mellitus, thyroxine in cretinism and myxoedema, etc.
Mechanism of drug action PH1.5
Nonreceptor-mediated mechanism of action of drugs
- 1.
By physical action:
- a.
Osmosis: Some drugs act by exerting an osmotic effect, e.g. 20% mannitol in cerebral oedema and acute congestive glaucoma.
- b.
Adsorption: Activated charcoal adsorbs toxins; hence, it is used in the treatment of drug poisoning.
- c.
Demulcent: Cough syrup produces a soothing effect in pharyngitis by coating the inflamed mucosa.
- d.
Radioactivity: Radioactive isotopes emit rays and destroy the tissues, e.g. 131 I in hyperthyroidism.
- a.
- 2.
By chemical action:
- a.
Antacids are weak bases – they neutralize gastric acid – useful in peptic ulcer.
- b.
Metals like iron, copper, mercury, etc. are eliminated from the body with the help of chelating agents. These agents trap metals and form water-soluble complexes, which are rapidly excreted from the body, e.g. dimercaprol (BAL) in arsenic poisoning, desferrioxamine in iron poisoning and d-penicillamine in copper poisoning.
- a.
- 3.
Through enzymes: Some drugs act by inhibiting the enzyme activity.
- a.
Angiotensin-converting enzyme (ACE) inhibitors, such as captopril, enalapril, etc. act by inhibiting ACE. They are used in the treatment of hypertension, congestive heart failure, etc.
- b.
Xanthine and hypoxanthine are oxidized to uric acid by the enzyme xanthine oxidase, which is inhibited by allopurinol. Allopurinol (competitive inhibitor) is used in the treatment of chronic gout to reduce the synthesis of uric acid.
- a.
- 4.
Through ion channels: Some drugs directly bind to ion channels and alter the flow of ions, e.g. local anaesthetics block sodium channels in neuronal membrane to produce local anaesthesia.
- 5.
Through antibody production: Vaccines produce their effect by stimulating the formation of antibodies, e.g. vaccine against tuberculosis (BCG), oral polio vaccine, etc.
- 6.
Transporters: Some drugs produce their effect by binding to transporters. Selective serotonin reuptake inhibitors (SSRIs) → bind to 5-HT transporter → block 5-HT reuptake into neurons → antidepressant effect.
- 7.
Others: Drugs, like colchicine, bind to tubulin and prevent migration of neutrophils (hence useful in acute gout).
Receptor-mediated mechanism of action of drugs
Receptors are macromolecules, present either on the cell surface, cytoplasm or in the nucleus with which the drug binds and interacts to produce cellular changes.
For example, adrenergic receptors (α and β), cholinergic receptors (muscarinic and nicotinic), opioid receptors, etc.
Affinity: The ability of the drug to get bound to receptor is known as affinity.
Intrinsic activity: The ability of the drug to produce pharmacological action after combining with the receptor is known as intrinsic activity of the drug.
Agonist: A drug that is capable of producing pharmacological action after binding to the receptor is called an agonist.
Agonist has high affinity + high intrinsic activity (e.g. morphine and adrenaline).
Antagonist: A drug that prevents binding of agonist to its receptor or blocks its effect/s is called an antagonist. It does not by itself produce any effect.
Competitive antagonist has high affinity without intrinsic activity (e.g. naloxone and atropine). It produces receptor blockade.
Partial agonist: A drug that binds to the receptor but produces an effect less than that of an agonist is called partial agonist. It inhibits the effect of agonist.
Partial agonist has affinity + less intrinsic activity (e.g. pindolol and buprenorphine).
Inverse agonist: It has full affinity towards the receptor but produces effect opposite to that of an agonist, e.g. benzodiazepines (BZDs) produce antianxiety and anticonvulsant effects by interacting with BZD receptors, but β-carbolines act as inverse agonist at BZD receptor and produce anxiety and convulsions.
Inverse agonist has affinity + intrinsic activity between 0 and –1 (e.g. β-carboline).
Receptor families ( table 1.5 ) PH1.5
- 1.
Ligand-gated ion channels (inotropic receptors)
Table 1.5 ■Characteristics of various receptor familiesLigand-gated ion channels G protein-coupled receptors Enzymatic receptors Nuclear receptors Location Membrane Membrane Membrane Intracellular Effector Ion channel Channel or enzyme Enzyme Gene transcription Examples Nicotinic, GABA A receptors Muscarinic, adrenergic receptors Insulin epidermal growth factor receptors Steroid, thyroid hormone receptors Time required for response Milliseconds Seconds Minutes to hours Hours - 2.
G protein-coupled receptors (GPCRs; metabotropic receptors)
- 3.
Enzymatic receptors
- 4.
Receptor-regulating gene expression (transcription factors) or the nuclear receptor
Ligand-gated ion channels (inotropic receptors).
Examples are nicotinic (N M ) acetylcholine receptors at neuromuscular junction, GABA (gamma amino butyric acid) and glutamate receptors in the CNS.
The onset of action of a drug is fastest through this receptor.
G protein-coupled receptors (GPCRs, metabotropic receptors).
GPCRs are transmembrane receptors which control cell function via adenylyl cyclase, phospholipase C, ion channels, etc. They are coupled to intracellular effectors through G proteins. G proteins are membrane proteins and have three subunits (α, β, γ) with GDP bound to α subunit.
The agonist that binds to the receptor is the first messenger. It results in the formation or recruitment of molecules (second messengers) that initiate the signalling mechanism in a cell. Examples of second messengers are cAMP (generated by adenylyl cyclase), cGMP (generated by guanylyl cyclase), Ca 2+ , IP 3 -DAG (generated by phospholipase C), nitric oxide, etc.
Transmembrane enzyme-linked receptors.
Transmembrane enzyme-linked receptors have enzymatic activity in their intracellular portion. The enzyme is mainly tyrosine kinase, e.g. receptor tyrosine kinases for insulin, epidermal growth factor, etc.).
Transmembrane JAK (Janus kinase)-STAT (signal transducer and activator of transcription) receptors, e.g. receptors for cytokines, growth hormone, etc. These receptors do not have intrinsic enzymatic activity in their intracellular part. On activation, they dimerize followed by their binding to kinases in the cytoplasm, e.g. JAK → phosphorylates tyrosine residues on the receptor → binding of receptor to STAT which gets phosphorylated → dissociation of STAT from receptor → binds to gene to alter transcription.
Nuclear receptors – regulate gene expression.
Examples: receptors for thyroxine, vitamins A and D, sex steroids and glucocorticoids.
Steroids → bind to receptors in cytoplasm → steroid-receptor complex → migrates to nucleus → binds to specific site on the DNA → regulate protein synthesis → response
Regulation of receptors
Receptors can be regulated by various mechanisms resulting in either their upregulation or downregulation ( Table 1.6 ).
| Receptor downregulation | Receptor upregulation |
|---|---|
| Prolonged use of agonists ↓ ↓↓ Receptor number and sensitivity ↓ ↓↓ Drug effect For example, chronic use of salbutamol downregulates β2-adrenoceptors, which may be responsible for decreased effect of salbutamol in asthmatics. | Prolonged use of antagonists ↓ ↑↑ Receptor number and sensitivity; On sudden stoppage of the antagonist ↓ ↑↑ Response to agonist For example, when propranolol is stopped after prolonged use, some patients experience symptoms, such as nervousness, anxiety, palpitation, tachycardia, rise in BP, increased incidence of angina or even myocardial infarction may be precipitated. This is due to upregulation or supersensitivity of β-adrenoceptors to catecholamines. Therefore, propranolol should not be discontinued abruptly. |
Dose–response relationship
The pharmacological effect of a drug depends on its concentration at the site of action, which in turn is determined by dose of the drug administered. Such a relationship is called ‘dose–response relationship’.
Types of dose–response curves
- 1.
Graded dose–response: This curve when plotted on a graph takes the form of a rectangular hyperbola, whereas log dose–response curve (DRC) is sigmoid shaped ( Fig. 1.7 A and B).
Fig. 1.7 (A) Dose–response curve. (B) Log dose–response curve. (C) Quantal dose–response curve. - 2.
Quantal DRC: Certain pharmacological effects which cannot be quantified but can only be said to be present or absent (all or none) are called as quantal responses, e.g. a drug causing ovulation ( Fig. 1.7 C).
Therapeutic index
Therapeutic index (TI) is an index of drug safety.
It is the ratio of median lethal dose to the median effective dose ( Fig. 1.8 ).
- 1.
LD 50 : It is the dose of a drug, which is lethal for 50% of the population.
- 2.
ED 50 : It is the dose of drug, which produces the desired effect in 50% of the population.
Higher the value of therapeutic index, safer is the drug, e.g. penicillin G has a high therapeutic index; digitalis, lithium and phenytoin have narrow therapeutic index.
Drug potency
The amount of a drug required to produce a desired response is called potency of the drug. Lower the dose required for a given response, more potent is the drug, e.g. analgesic dose of morphine is 10 mg and that of pethidine is 100 mg. Therefore, morphine is ten times more potent than pethidine as an analgesic. DRC of drug A (morphine) and drug B (pethidine, rightward DRC) as analgesic is compared ( Fig. 1.9 ).
Drug efficacy
It is the maximum effect of a drug, e.g. morphine is more efficacious than aspirin as an analgesic ( Fig. 1.10 ). DRC of drug A (morphine) and drug B (aspirin) as an analgesic is compared.
Therapeutic range
It is the range of concentration of the drug which produces desired response with minimal toxicity.
Combined effect of drugs
A combination of two or more drugs can result in an increase or a decrease in response.
Increased response
- 1.
Additive effect: The combined effect of two or more drugs is equal to the sum of their individual effect.
Effect of drugs A + B = Effect of drug A + Effect of drug B
For example, combination of ibuprofen and paracetamol as analgesic.
- 2.
Potentiation (supra-additive): The enhancement of action of one drug by another drug which is inactive is called potentiation.
Effect of drugs A + B > Effect of drug A + Effect of drug B
For example, levodopa + carbidopa; acetylcholine + physostigmine.
Carbidopa and physostigmine inhibit breakdown of levodopa and acetylcholine, respectively, thus enhancing their effects.
- 3.
Synergism: When two or more drugs are administered simultaneously, their combined effect is greater than that elicited by either drug alone.
For example, sulphamethoxazole + trimethoprim; pyrimethamine + sulphadoxine.
Decreased response (drug antagonism)
In antagonism, the effect of one drug is decreased or abolished in the presence of another drug.
- 1.
Physical antagonism: The opposing action of two drugs is due to their physical property, e.g. adsorption of alkaloids by activated charcoal – useful in alkaloid poisoning.
- 2.
Chemical antagonism: The opposing action of two drugs is due to their chemical property, e.g. antacids are weak bases; they neutralize gastric acid and are useful in peptic ulcer; chelating agents complex metals and are useful in heavy metal poisoning (dimercaprol in arsenic poisoning).
- 3.
Physiological (functional) antagonism: Here, two drugs act at different receptors or by different mechanisms on the same physiological system and produce opposite effects, e.g. insulin and glucagon on blood sugar; adrenaline and histamine on bronchial smooth muscle – histamine produces bronchoconstriction (via histamine receptors), whereas adrenaline produces bronchodilatation by acting through adrenergic (β 2 ) receptors – hence, adrenaline helps to reverse bronchospasm in anaphylactic shock.
- 4.
Receptor antagonism: The antagonist binds to the same receptor as the agonist and inhibits its effects. It can be competitive or noncompetitive.
- a.
Competitive antagonism (equilibrium type) : In competitive antagonism, both agonist and the antagonist bind reversibly to same site on the receptor.
For example,
Equilibrium type of competitive antagonism can be overcome (reversible) by increasing concentration of the agonist. The log DRC of the agonist shows a rightward parallel shift in the presence of competitive antagonist ( Fig. 1.11 ).
Fig. 1.11 Competitive antagonism. (Adapted from Alfred Gilman Sr. and Louis S. Goodman: Goodman & Gilman’s The Pharmacological Basis of Therapeutics , 12th edition, Mcgraw Hill, 2018.)Nonequilibrium antagonism : The antagonist binds to the same site on the receptor as agonist but binding is irreversible. The antagonist forms strong covalent bond with the receptor, e.g. phenoxybenzamine is an irreversible antagonist of adrenaline at α receptors.
- b.
Noncompetitive antagonism: The antagonist binds to a different site on the receptor and prevents the agonist from interacting with the receptor. In this type, the antagonistic effect cannot be overcome by increasing the concentration of the agonist. There is a flattening of the DRC in noncompetitive antagonism, e.g. diazepam and bicuculline ( Fig. 1.12 ).
Fig. 1.12 Noncompetitive antagonism. (Adapted from Alfred Gilman Sr. and Louis S. Goodman: Goodman & Gilman’s The Pharmacological Basis of Therapeutics , 12e.)
- a.
Factors modifying drug action
There are a number of factors which can influence drug response. Individuals may often show quantitative variations in drug response but rarely show qualitative variations. The important factors are described in Table 1.7 .
| Drug factors | Patient factors |
|---|---|
|
|
|
|
|
|
| |
| |
| |
| |
| |
|
Drug factors
- 1.
Route of administration: When a drug is administered by different routes, it commonly exhibits quantitative variations, but sometimes it may also result in qualitative variations in response.
- a.
Quantitative variation: Oral dose of drugs are usually larger than intravenous dose (since i.v. route produces 100% bioavailability), e.g. for analgesic effect, intravenous dose of morphine required is 5–10 mg whereas oral dose is 30–60 mg. Onset of drug action following intravenous administration is rapid.
- b.
Qualitative variation: The drug may produce an entirely different response when administered by different routes, e.g. magnesium sulphate administered orally produces purgative effect; parenterally, it causes CNS depression and on local application reduces oedema in the inflamed area.
- a.
- 2.
Presence of other drugs: See addition, potentiation, synergism and antagonism.
- 3.
Cumulation: If the elimination of a drug is slow, then repeated administration of such drug will result in its accumulation in the body causing toxicity, e.g. digoxin, emetine and chloroquine.
Patient factors
- 1.
Age: In neonates, metabolizing function of liver and excretory function of kidney is not fully developed, e.g. chloramphenicol can cause grey baby syndrome when given to neonates as the metabolizing enzymes are not fully developed. In adults, penicillin G is given 6 hourly, but in infants it is given 12 hourly as the excretory function is not completely developed. In the elderly, renal and hepatic functions progressively decline. The incidence of adverse effect of drugs is also relatively more, and hence drug doses have to be reduced accordingly, e.g. dose of aminoglycosides in elderly is less than normal adult dose.
The dose of a drug for a child can be calculated as follows:
- 2.
Body weight and body surface: An average dose of a drug is usually calculated in terms of body weight (mg/kg).
In obese individuals and in patients with dehydration or oedema, dose calculation on the basis of body weight is not very appropriate. A more accurate method for calculating a dose is on the basis of the body surface area (BSA) of the patient. Nomograms are available to calculate BSA from height and weight of the patient.
Since it is inconvenient to calculate BSA, dose is routinely calculated on body weight basis. Dose of anticancer drugs and a few other drugs are calculated on the basis of BSA.
- 3.
Sex: Drugs like β blockers, diuretics and clonidine can cause decreased libido in males.
- 4.
Diet and environmental factors: Milk reduces absorption of tetracyclines; fatty meal increases the absorption of griseofulvin (antifungal agent). Cigarette smoke induces hepatic microsomal enzymes and increases metabolism of drugs, such as theophylline. So, the dose of the drug administered may be inadequate in smokers.
- 5.
Genetic factor: For example, fast and slow acetylators of isoniazid, prolonged succinylcholine apnoea, primaquine induced haemolysis in G6PD deficiency individuals (see p. 17 under metabolism). Other examples are as follows-
- ■
Acute porphyria
Barbiturates may precipitate attacks of acute intermittent porphyria in susceptible individuals by inducing ALA (aminolevulinic acid) synthase enzyme that catalyses the production of porphyrins.
- ■
Malignant hyperthermia
In some patients, dangerous rise in body temperature (malignant hyperthermia) may occur especially when halothane–succinylcholine combination is used due to genetic abnormality.
- ■
In person with shallow anterior chamber/and or narrow iridocorneal angle, mydriatics may precipitate acute congestive glaucoma.
- ■
There is an increased risk of bleeding with coumarin anticoagulants due reduced activity of metabolizing enzyme, CYP2C9.
- ■
- 6.
Psychological factor: Personality of the doctor as well as the patient can affect response to a drug. Some patients respond to inert dosage forms (placebo) in conditions like pain, bronchial asthma, anxiety, etc.
Placebo effect: ‘ Placebo ’ is a Latin term that means ‘I will please’. It is a dummy medicine having no pharmacological activity. The effect produced by placebo is called placebo effect. Sugar tablets and distilled water injection are used as placebos.
- 1)
Uses
- a)
Placebos are used for the relief of subjective symptoms like anxiety, headache, tremors, pain, insomnia, etc.
- b)
Placebos are used in clinical trials in order to minimize bias.
- a)
- 2)
Factors affecting placebo effect are:
- a)
Patient factor: Patients with neurotic symptoms often respond to placebos.
- b)
Drug factor: The placebo response can be affected by the physical presentation or route of administration of the drug, e.g. colourful tablets, such as red, blue, green and injectable preparations give better placebo effect.
- c)
Doctor factor: Personality of the doctor, motivation, way of instruction, doctor–patient relationship, etc. are important factors that also affect response to placebo.
- a)
- 1)
- 7.
Pathological states:
- a.
GI disorders : Achlorhydria reduces the absorption of weakly acidic drugs in stomach by causing their ionization. In malabsorption syndrome, absorption of some drugs is reduced.
- b.
Liver disease : In chronic liver diseases, metabolism of drugs is greatly reduced. This will increase bioavailability of drugs having high first-pass metabolism, e.g. propranolol.
- c.
Renal failure : Clearance of drugs that are excreted through kidney is impaired, e.g. the incidence of nephrotoxicity and ototoxicity with aminoglycosides is more in the presence of renal failure.
- d.
Absorption of iron from the gut is increased in iron deficiency anaemia.
- a.
- 8.
Tolerance: It means ‘need for larger doses of a drug to produce a given response’. Tolerance develops to nasal decongestant effect of ephedrine on repeated use. Patients on organic nitrates for angina develop tolerance on long-term therapy. Tolerance is commonly seen with drugs like morphine, alcohol, amphetamine, etc.
- a.
Types of tolerance
- b.
Mechanism of development of tolerance: It could be pharmacokinetic or pharmacodynamic tolerance.
- 1)
Pharmacokinetic tolerance (dispositional tolerance): It is due to reduced concentration of the drug at the site of action – may be as a result of decreased absorption, increased metabolism and excretion. For example, rifampin induces the metabolizing enzyme of oral contraceptives, enhances their metabolism, leading to contraceptive failure.
- 2)
Pharmacodynamic tolerance (functional tolerance): The drug effect is reduced, which may be due to downregulation of receptors or decrease in receptor-coupled signal transduction. Repeated use of opioids, barbiturates, etc. results in the development of tolerance due to decrease in the number of receptors (downregulation).
- 1)
- c.
Cross-tolerance: The phenomenon of tolerance exhibited by closely related (structural and mechanistic) drugs is called cross-tolerance, e.g. among nitrates, among opioids, between ether and alcohol.
- d.
Tachyphylaxis ( tachy = rapid; phylaxis = protection; acute tolerance ): Repeated use of certain drugs at short intervals may result in rapid decrease in pharmacological response. This is known as tachyphylaxis or acute tolerance, e.g. tyramine, ephedrine and amphetamine. These drugs act by releasing noradrenaline from adrenergic nerve endings. Repeated administration of the drug causes gradual depletion of the neurotransmitter and hence reduction in the response ( Fig. 1.13 ).
Fig. 1.13 Tachyphylaxis. BP, blood pressure.
- a.
- 9.
Drug dependence: See p. 39.
Drug interactions PH1.8
When two or more drugs are given simultaneously, the effects of one drug may be altered by another drug. Drug interactions can occur in vitro (outside the body) or in vivo (inside the body).
Drug interactions can result in either beneficial or harmful effects.
Pharmaceutical interactions: These can occur as a result of incompatibility (physical or chemical) of a drug with an intravenous solution or when two or more drugs are mixed in the same syringe/i.v. infusion. This may result in precipitation or inactivation of one or more drugs.
Phenytoin should not be administered in dextrose solution as it gets precipitated.
Dextrose solution is not suitable for i.v. infusion of ampicillin as it is unstable at acidic pH of dextrose.
Gentamicin and carbenicillin should not be given in the same infusion as it may result in loss of potency.
Pharmacokinetic interactions: These occur when one drug alters the absorption, distribution, metabolism or excretion of another drug.
- ■
Absorption : Antacids (containing aluminium, magnesium and calcium), iron, etc. interfere with the absorption of tetracyclines by forming unabsorbable complexes with it.
Some drugs affect absorption of other drugs by altering GI motility. Metoclopramide increases the rate of gastric emptying and promotes absorption of aspirin.
- ■
Distribution : Plasma protein binding can cause displacement interactions. More than one drug can bind to the same site on plasma protein. The drug with higher affinity will displace the one with lower affinity. This results in increase in concentration of unbound drug, e.g. salicylates displace warfarin from binding sites resulting in increased free warfarin levels and enhanced anticoagulant effect.
- ■
Metabolism : This occurs when metabolism of one drug is increased (enzyme induction) or decreased (enzyme inhibition) by another drug, e.g. carbamazepine induces the metabolizing enzyme of warfarin, thus enhancing its metabolism and leading to decreased anticoagulant effect. Erythromycin inhibits the metabolizing enzyme of carbamazepine and may increase its toxicity.
- ■
Excretion : Most of them occur in kidney.
- ■
Salicylates interfere with the excretion of methotrexate and potentiate its toxicity.
- ■
Probenecid decreases renal tubular secretion of penicillins/cephalosporins and prolongs their duration of action (beneficial interaction).
- ■
Pharmacodynamic interactions: The interaction is due to action of drugs on receptors or physiological system. This may result in either additive, synergistic or antagonistic effects (see pp. 29, 30). The interaction may result in harmful effects, e.g. enhanced nephrotoxicity seen with the concurrent use of aminoglycosides and amphotericin B; it may also result in beneficial effect, e.g. levodopa and carbidopa in parkinsonism.
Rational use of medicines
According to WHO, rational use of medicines requires that ‘ patients receive medications appropriate to their clinical needs in doses that meet their own individual requirements for an adequate period of time and at the lowest cost to them and their community ’.
It involves the administration of right drug, right dose, right duration, right cost to the right patient.
Examples of irrational prescribing
- ■
Drug not prescribed as per standard treatment guidelines.
- ■
Unnecessary use of drugs, e.g. antibiotics for viral infections.
- ■
Underuse of drugs, e.g. not prescribing oral rehydration solution in acute diarrhoea.
- ■
Incorrect use of a drug, e.g. selection of wrong drug, use of incorrect route and dose of a drug.
- ■
Use of medicines with doubtful efficacy, e.g. appetite stimulants.
- ■
Prescribing banned drugs, e.g. cisapride.
- ■
Use of irrational combinations, e.g. ampicillin and cloxacillin for staphylococcal infections.
- ■
Prescribing expensive medicines unnecessarily when cheaper, equally effective drugs are available.
- ■
Polypharmacy.
Hazards of irrational use of drugs
- ■
Therapeutic failure.
- ■
Increased incidence of adverse drug reactions (ADRs).
- ■
Emergence of drug-resistant microorganisms.
- ■
Increase in cost of treatment.
- ■
Financial burden to society.
- ■
Loss of patient’s faith in the doctor.
Rational prescribing (WHO)
- ■
A diagnosis has to be made.
- ■
The problem has to be defined.
- ■
The therapeutic goals to be achieved, e.g. relief of symptoms, cure, etc. has to be set.
- ■
The right drug - appropriate route, dose and duration of treatment has to be selected. Write a complete prescription.
- ■
Proper instructions and information about the drug should be given.
- ■
Monitor therapy.
Adverse drug effects PH1.7
Adverse effect
Adverse effect is defined as any undesirable or unwanted effect of a drug. The WHO-suggested definition of ADR and adverse event (AE) are as follows:
ADR: Any response which is noxious, unintended and which occurs at doses normally used in humans for prophylaxis, diagnosis or therapy of disease, or for modification of physiological function .
AE: Any untoward medical occurrence that may present during treatment with a pharmaceutical product but which does not necessarily have causal relationship with the treatment .
Types of adverse drug reactions
Predictable reactions (type A or augmented reactions)
These are predictable reactions to a drug which are related to its pharmacological actions. They include side effects, secondary effects and toxic effects.
Unpredictable reactions (type B or bizarre reactions)
These are nondose-related unpredictable reactions to a drug. They are not related to the pharmacological actions of the drug. Allergic reactions and idiosyncrasy are unpredictable reactions.
Predictable reactions
- ■
Side effects: These are unwanted pharmacological effects of a drug, that are seen with therapeutic doses, e.g. atropine used in the treatment of heart block also produces dryness of mouth, blurring of vision, urinary retention, etc., which are the side effects.
- ■
Secondary effects: The primary action of a drug may result in other effects, e.g. immunosuppression by corticosteroids can lead to development of opportunistic infections, e.g. oral candidiasis.
- ■
Toxic effects: These are the effects of a drug, which are either due to overdosage or chronic use, e.g. bleeding due to chronic use/overdosage of anticoagulants and nephrotoxicity with aminoglycosides especially in patients with renal failure.
Unpredictable reactions
- ■
Drug allergy: It is an abnormal response (local or systemic), mediated by immune system, to a drug/foreign antigen. Different types of hypersensitivity reactions are discussed below.
- ■
Those associated with humoral antibodies: types I, II and III.
- ■
Those associated with cell-mediated immunity: type IV (delayed hypersensitivity).
- ■
Type I hypersensitivity (immediate type, anaphylactic) reactions
It is a rapidly occurring reaction, hence called immediate hypersensitivity reaction. The manifestations are itching, urticaria, hay fever, asthma or even anaphylactic shock. Itching, rhinitis and urticaria are treated with antihistamines,
Anaphylactic shock is a medical emergency and should be treated promptly with:
- 1.
Inj. adrenaline (1:1000) 0.3–0.5 mL intramuscularly.
- 2.
Inj. hydrocortisone 100–200 mg intravenously.
- 3.
Inj. pheniramine 45 mg intramuscularly/intravenously.
- 4.
Maintenance of patent airway, intravenous fluids.
Type II hypersensitivity (cytotoxic) reactions
The antibodies (IgG and IgM) react with cell-bound antigen and cause activation of complement, which destroys the cells.
Examples are: blood transfusion reactions, haemolytic anaemias produced by quinine, quinidine, cephalosporins, etc.
Type III hypersensitivity (Arthus, serum sickness) reactions
In this type of reaction, antibodies involved are mainly IgG.
For example, serum sickness (fever, urticaria, joint pain, lymphadenopathy) with penicillins and sulphonamides; acute interstitial nephritis with nonsteroidal anti-inflammatory drugs (NSAIDs) and Stevens–Johnson syndrome with sulphonamides.
Type IV hypersensitivity (cell-mediated or delayed hypersensitivity) reactions
It is mediated by sensitized T lymphocytes. Reexposure to the antigen leads to a local inflammatory response. The manifestations usually occur 1–2 days after exposure to the sensitizing antigen, e.g. contact dermatitis due to local anaesthetic creams, topical antibiotics and antifungal agents.
Types II, III and IV reactions are treated with glucocorticoids.
- ■
Idiosyncrasy
It is usually a genetically determined abnormal reaction to drugs, e.g. aplastic anaemia caused by chloramphenicol, prolonged succinylcholine apnoea, haemolytic anaemia seen with primaquine and sulphonamides.
- ■
Drug dependence PH1.22, PH1.23
WHO defines drug dependence as ‘ a state, psychic and sometimes also physical, resulting from the interaction between a living organism and a drug characterized by behavioural and other response that always include a compulsion to take the drug on a continuous or periodic basis in order to experience its psychic effects and sometimes to avoid the discomfort of its absence ’, e.g. opioids, alcohol, barbiturates, amphetamine, etc. The dependence could be psychological or physical.
- a.
Psychological dependence: There is an intense desire to continue taking the drug as the patients feel that their well-being depends on the drug.
- b.
Physical dependence: Repeated drug use produces physiological changes in the body, which makes continuous presence of the drug in the body necessary to maintain normal function. Abrupt stoppage of the drug results in an imbalance wherein the body has to readjust to the absence of the drug resulting in the development of signs and symptoms known as withdrawal syndrome . The withdrawal signs and symptoms are generally opposite to the effects produced by the drug.
Principles of treatment of drug dependence are:
- 1.
Hospitalization.
- 2.
Substitution therapy: For example, methadone substitution for morphine addiction.
- 3.
Aversion therapy: Disulfiram for alcohol addiction.
- 4.
Psychotherapy
- 5.
General measures: Maintain nutrition, family support and rehabilitation.
- ■
Iatrogenic diseases
It is physician-induced disease (‘ iatros ’ is a Greek word, means ‘physician’) due to drug therapy, e.g. parkinsonism due to metoclopramide; acute gastritis and peptic ulcer due to NSAIDs.
- ■
Teratogenicity
Certain drugs when given during pregnancy may cross the placenta and produce various dangerous effects in the fetus ( Table 1.8 ). This is called teratogenesis.
Table 1.8 ■Teratogenic effects of some drugs (Note the ‘T’s)Drug Teratogenic effect Thalidomide Phocomelia Tetracyclines Yellowish discolouration of teeth Antithyroid drugs Fetal goitre Administration of drugs during early pregnancy (conception to 16 days) could result in abortion; during 2–8 weeks of gestation, it can affect organogenesis and produce structural abnormalities; during second and third trimester, drugs can affect growth and development of the fetus. Hence, drug administration during pregnancy should be restricted.
The USFDA (Food and Drug Administration) had placed drugs in various categories (A, B, C, D, X) depending on the risk of the drug to cause birth defects. Category X drug (e.g. warfarin, methotrexate) was contraindicated for use during pregnancy as risk to fetus was proven and outweighed benefits of its use. This system is being replaced by a revised labelling rule which will provide latest information about a drug pertaining to its use during pregnancy.
- ■
Carcinogenicity and mutagenicity
The ability of a drug to cause cancer is carcinogenicity and the agent is known as carcinogen. The abnormalities of genetic material in a cell produced by a drug is known as mutagenicity, e.g. anticancer drugs and oestrogens.
- ■
Photosensitivity reactions
It is a drug-induced cutaneous reaction (photoallergy/phototoxicity) following exposure to ultraviolet radiation. Sulphonamides cause photoallergy on exposure to light; they produce dermatitis due to immune response (cell mediated). Doxycycline and fluoroquinolones can cause phototoxicity – a local reaction (erythema, blisters) occurs on exposure to UV light. Use of sunscreen and avoidance of exposure to sunlight is advised. Calamine lotion and topical steroids are used for treatment.
- ■
Hepatotoxicity
Some of the hepatotoxic drugs are isoniazid, rifampicin, pyrazinamide, halothane, paracetamol, etc.
- ■
Nephrotoxicity (Vancomycin, aminoglycosides, cisplatin, cyclosporine, amphotericin B, tetracyclines [Fanconi syndrome], indinavir, gold salts, nystatin, etc. are nephrotoxic drugs) *
* Mnemonic for nephrotoxic drugs: VACATION.
- ■
Ototoxicity
It can occur with aminoglycosides, loop diuretics, cisplatin, etc.
- ■
Ocular toxicity
Ethambutol, chloroquine, glucocorticoids, etc. can cause ocular toxicity.
Pharmacovigilance.
It is the ‘ science and activities relating to detection, assessment, understanding and prevention of adverse effects or any other possible drug-related problems ’ (WHO). The aim of pharmacovigilance is to improve patient care and safety related to use of drugs, promote rational use of medicines, develop regulations for use of drugs and educate health care professionals about ADRs. PH1.6
Causality assessment: Some of the commonly used tools for causality assessment are Naranjo’s scale and WHO scale.
The National Pharmacovigilance Centre is located at Ghaziabad. The International Centre is Uppsala Monitoring Centre in Sweden. Any health care professional, e.g. doctors, dentists, nurses and pharmacists can report a suspected adverse drug event. Patients can also report ADRs.
Treatment of poisoning PH1.52
Toxicology is the study of poisons – their actions, detection, prevention and treatment of poisoning. All poisoning cases require hospitalization and careful observation till recovery. Poisoning may be suicidal, homicidal or accidental. All cases of poisoning are medico-legal cases; hence, the police should be informed.
General management
- 1.
H ospitalization.
- 2.
A irway should be cleared. In comatose patients, there is danger of respiratory obstruction by tongue, secretions and aspiration of vomitus. Hence, patient should be turned to his left lateral side. A cuffed endotracheal tube should be inserted and secretions should be aspirated regularly.
- 3.
B reathing should be assessed. If there is hypoxaemia, oxygen should be given. Patient may need mechanical ventilation if there is respiratory insufficiency.
- 4.
C irculation should be assessed (pulse rate and blood pressure) and an i.v. (intravenous) line should be maintained.
- 5.
To prevent further absorption of poison:
- a.
Inhaled poisons (gases): Patient should be moved to fresh air.
- b.
Contact poisons: Contaminated clothes should be removed and the body part should be washed with soap and water.
- c.
Ingested poisons: G astric lavage can limit the absorption if done within 2–3 hours of poisoning. If patient is unconscious, endotracheal intubation should be done before gastric lavage. Gastric lavage is usually done with normal saline. Other solutions used are lukewarm water, potassium permanganate solution, sodium bicarbonate, etc. Lavage should be repeated till the returning fluid is clear. After the lavage, activated charcoal is administered which adsorbs many drugs and poisons (physical antagonism). Activated charcoal has a large surface area and is highly porous to bind with poisonous material. Gastric lavage should not be carried out in case of poisoning due to corrosives (except carbolic acid), petroleum products (kerosene), convulsants, etc.
Mustard, common salt, ipecac syrup, etc. can be used to induce vomiting and prevent further absorption of ingested poisons. However, this method is rarely practiced now.
Laxatives like magnesium sulphate or citrate can be used orally to promote elimination of the ingested poison. Oral polyethylene glycol electrolyte solution can be used for whole bowel irrigation of the GI tract in case of poisoning due to iron, lithium, cocaine, heroin, foreign bodies, etc.
- a.
- 6.
To promote elimination of absorbed portion of the drugs:
- a.
D iuretics (i.v. mannitol or furosemide) are used to promote the elimination of absorbed portion of the drug. Renal elimination of some of the drugs can be increased by altering the pH of urine, e.g. alkalinization of urine in salicylate poisoning and acidification of urine in amphetamine poisoning.
- b.
D ialysis is used in cases of severe poisoning, e.g. lithium, aspirin, methanol, etc.
- a.
- 7.
Symptomatic treatment: Intravenous diazepam 5–10 mg if there are convulsions and external cooling for hyperpyrexia.
- 8.
Maintenance of f luid and e lectrolyte balance: Hyponatraemia should be treated with i.v. normal saline and hypernatraemia with i.v. furosemide. Hypokalaemia is treated with potassium chloride, oral or slow i.v. infusion. Oral potassium chloride should be diluted in a tumbler of water to prevent intestinal ulceration. Potassium chloride should be given slow intravenously as it has cardiac depressant effect. Rapid injection can cause cardiac arrest and death. Thiazides or furosemide can be used to treat mild hyperkalaemia. Severe hyperkalaemia is treated with 10% calcium gluconate intravenously. Intravenous sodium bicarbonate is used to treat metabolic acidosis.
Note: Mnemonic for general management of poisoning: A to H.
Specific management
Antidotes for some poisons are listed in Table 1.9 .
| Poison | Antidote |
|---|---|
| Alkalies | Dilute acetic acid (vinegar) |
| Organophosphorus compounds | Atropine |
| Morphine (opioids) | Naloxone |
| Atropine | Physostigmine |
| Benzodiazepines | Flumazenil |
| Carbamates | Atropine |
| Cyanide | Sodium nitrite and sodium thiosulphate |
| Methanol | Fomepizole, ethyl alcohol |
| Paracetamol | N -acetylcysteine |
| Heparin | Protamine sulphate |
| Warfarin | Vitamin K 1 (phytonadione) |
| Iron compounds | Desferrioxamine |
Poison information centres
WHO has established poison information centres in AIIMS, New Delhi and Ahmedabad. Computer software on poisons (INTOX) is used in these centres. Regional centres are in Chennai and Cochin (POISONDEX). These centres provide information about toxicity assessment and treatment over the phone throughout the day.
Pharmacoeconomics PH1.60
It is a scientific discipline that deals with the evaluation of cost and consequences of drug therapy or other interventions to health care system and society. The commonly used pharmacoeconomic analytical methods are cost minimization analysis, cost-effectiveness analysis and cost-benefit analysis.
New drug development PH1.64
Preclinical studies in animals: Before undertaking clinical trials, sufficient data about the drug must be obtained by testing it in animals. Animal studies generate pharmacodynamic, pharmacokinetic and toxicological data of the drug.
Toxicity studies
Acute toxicity studies
Acute toxicity is carried out in two animal species (one rodent, one nonrodent). Single, graded doses are administered to small groups of animals using two routes – one that is to be used in humans. It is done to determine the general behaviour and median lethal dose (LD 50 ) following exposure to the test drug. LD 50 is the dose required to kill 50% of the animals. It is determined in a 24-hour period after administration of the drug.
Subacute toxicity studies
These are done in two species of animals to determine the maximum tolerated dose, identify target organ of toxicity and nature of toxicities. The test drug is administered daily for a period depending on the duration of treatment in humans. Animals are examined for general effects (food intake, change in the body weight, etc.), biochemical and haematological parameters are monitored; histological examination is done.
Chronic toxicity studies
Drugs are administered in two species (one rodent and one nonrodent) for 6–12 months. Monitoring is done as in subacute toxicity studies.
Special toxicity studies
These include tests for carcinogenicity, mutagenicity and teratogenic effects of the drug. It also includes effects on reproduction.
Clinical trials PH1.64
After completion of preclinical testing of the drug, the company files an investigational new drug (IND) application with the regulatory authority for permission to test the drug in humans. A drug should be scientifically and ethically evaluated by testing in human beings for safety and efficacy prior to its use in man for therapeutic purposes. Such study in humans is referred to as clinical trial. The principles of bioethics should be upheld during clinical trials. They include autonomy, beneficence, nonmaleficence and justice. Clinical trials are conducted in four phases, I–IV. Usually, the information obtained from one phase is analysed before proceeding to the next phase.
Phase I
This phase involves testing of the drug in humans for the first time. It is carried out in about 10–100 participants. This is usually carried out in healthy volunteers. For drugs with potential toxicity, e.g. anticancer drugs, phase I trials are carried out in cancer patients. The main objective of this phase is to determine safety of the drug and the maximum tolerated dose. Pharmacokinetic and pharmacodynamic data can be obtained. It is usually carried out by a clinical pharmacologist. No blinding is done (open label study).
Phase II (therapeutic exploratory study)
It is carried out for the first time in patients with target disease for which the drug is intended to be used. It is conducted in about 50–500 patients and usually in three to four centres. The main objective of this phase is to assess the effectiveness of the drug and to determine effective dose range. Further evaluation of safety and pharmacokinetics is also done. The study is randomized and controlled, may be blinded.
Phase III (therapeutic confirmation trial)
The aim is to confirm the efficacy of the drug in large number of patients of either sex. It is conducted in multiple centres. It is generally randomized, double blind comparative trial. Further data on kinetics and drug interactions can be obtained. Permission for marketing the drug is granted after successful completion of phase III trials.
Phase IV (postmarketing surveillance)
Once the drug is approved for marketing, postmarketing surveillance is carried out to obtain additional data about benefit and risk of a drug following its long-term use in a larger number of patients. It provides information on adverse reactions, drug interactions, new indications and evaluation of different formulations. Postmarketing surveillance helps to estimate incidence of adverse reactions, detect previously unknown adverse reactions and identify risk factors for the adverse reactions. There are ADR monitoring centres in different parts of the country. The ADRs observed in the patient should be reported to these centres. The drug company has to submit postmarketing data for the drug at regular intervals to the regulatory agency to continue its use.
Besides clinical trials, other types of clinical studies are case control study, cohort study and meta-analysis.
Good clinical practice PH1.64
International Council for Harmonization – Good Clinical Practice (ICH–GCP) guidelines is an international ethical and scientific standard for designing, conducting, monitoring, terminating, auditing, reporting and recording trials. It ensures that the data generated from the trials is credible, accurate and the rights, integrity and confidentiality of the participants are protected.
Informed consent
Prior to enrolling the patient in the trial, the investigator should obtain informed consent from the subject. It is a process by which a subject voluntarily confirms his/her willingness to participate in a trial after having been informed of all aspects of the trial relevant to the subject’s decision to participate in the trial. The consent should be obtained by the investigator in the subject’s language without exerting undue influence. The informed consent is documented by means of a written, signed and dated (by both investigator and subject) informed consent form. If a subject is illiterate, his legally accepted representative or an impartial witness should be present during informed consent process. The thumb impression of the subject is taken and his legally accepted representative should sign and date the informed consent form. In case of young children and mentally ill patients, consent is obtained from their guardian or legal representative.
Ethics committee
It is a committee or board designated by the institution to review research proposals and conduct periodic review of research involving humans so as to ensure the protection of the rights and welfare of human subjects. The number of persons in an ethics committee is about 7–15. A minimum of five persons are required to form the quorum.
Composition
- 1.
Chairperson (from outside the institution to maintain independence of the committee)
- 2.
Basic medical scientists (preferably one pharmacologist)
- 3.
Clinicians
- 4.
Legal expert or retired judge
- 5.
Social scientist/philosopher/ethicist/theologist
- 6.
Lay person from the community
- 7.
Member secretary
Randomization
It is a process where the subjects are randomly assigned to treatment groups in a clinical trial using a chance mechanism. This is usually done by a computer. The investigator has no role in deciding the allocation of a particular treatment to a particular patient in the trial. Randomization is done to avoid bias in the constitution of trial group.
Blinding
The purpose of blinding in a trial is to eliminate bias. It is done to conceal the identity of the drug from the investigator and the subject. It could be single blind or double blind.
In a double blind trial, both the investigator and the subject do not know the identity of the drug administered to the subject. In a single blind trial, the subject is unaware of the identity of the drug administered to him. A randomized double blind trial is a standard design for most of the clinical trials.